Heterocyclic amphoteric compounds

ABSTRACT

Disclosed are a variety of amphoteric compounds having a heterocyclic quaternary nitrogen group. The heterocycle includes pyridines, piperidines, and pyrrolidines, and is linked to the hydrophobe via either an amide or an ester linkage. These hetereocyclic amphoteric compounds can be advantageously prepared in high yield and purity by a two-step chemoenzymatic process, and have excellent surfactant properties.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 14/518,517 filedon Oct. 20, 2014; the entire content of which is hereby incorporated byreference.

PARTIES TO JOINT RESEARCH AGREEMENT

Inventions disclosed or claimed herein were made pursuant to a JointResearch Agreement between Eastman Chemical Company and Johnson &Johnson Consumer & Personal Products Worldwide, a division of Johnson &Johnson Consumer Companies Inc.

FIELD OF THE INVENTION

The invention generally relates to heterocyclic amphoteric compounds.More particularly, the invention relates to heterocyclic quaternaryammonium carboxylates, compositions of such compounds, uses of suchcompounds, and processes for making them.

BACKGROUND OF THE INVENTION

There is an increasing industrial and societal need for safer and moreenvironmentally-friendly ingredients and methods for preparing thoseingredients. In particular, it is highly desirable to provide methodsthat reduce or eliminate the use of irritating or allergenic startingmaterials, that employ biocompatible reagents, and that optimally usestarting materials derived from a natural source or are“nature-equivalent.” This is of urgent interest in consumer-facingindustries, such as personal and household care.

One class of materials that may be approached in a “greener” manner issurfactants. Specifically, there is a need for new amphotericsurfactants that avoid using irritating or allergenic starting materialsand that are made in a more environmentally-friendly manner.

Amphoteric (or zwitterionic) surfactants are used throughout thepersonal and household care industries. They are classified as specialtyco-surfactants that complement the performance of primary surfactants.These co-surfactants also increase the mildness of the formulation byreducing irritation associated with purely ionic surfactants.

The most common zwitterionic surfactants are amido-amine based materialsproduced by a multi-step process from coconut or palm kernel oil andN,N-dimethylamino-3-propylamine (DMAPA). Various patents (U.S. Pat. No.3,280,179; U.S. Pat. No. 4,259,191) and publications (Parris et al., J.Am. Oil Chem. Soc., Vol. 54, pp. 294-296 (1977)) detail commonly usedpreparation methods for these types of materials. The processesgenerally involve the amidation of fatty acids with DMAPA at hightemperatures (150-175° C.). The intermediate fatty amino-amide is thenreacted with a hydrophilic species, e.g., sodium chloroacetate, to yieldthe betaine.

These processes have several drawbacks. For example, typical amidationprocesses require high temperatures for conversion and distillation toremove unreacted starting materials. These high reaction temperaturescan generate by-products and impart color to the products, requiringadditional steps to remove the by-products and the color.

Moreover, DMAPA is a known sensitizer, as is the correspondingamido-amine. Both are found in trace quantities in the finalformulation.

Thus, there is a need for amphoteric/zwitterionic surfactants that canbe prepared under milder conditions without the use of DMAPA or a DMAPAamide and that can retain or improve the performance properties oftraditional zwitterionic surfactants.

The present invention addresses this need as well as others, which willbecome apparent from the following description and the appended claims.

SUMMARY OF THE INVENTION

The invention is as set forth in the appended claims.

Briefly, in one aspect, the present invention provides a compound havingthe formula 1:

wherein

R is a C₃-C₂₃ hydrocarbyl group;

R¹ is a C₁-C₈ hydrocarbyl group;

HETN is a heterocyclic group selected from piperidine, pyridine,pyrollidine, quinoline, tetrahydroquinoline, indole, indoline,octahydroindole, acridine, octahydroacridine, andtetradecahydroacridine;

X is O or NH;

n is 0 or 1; and

m is 0 or 1 and is chosen to afford a quaternary heterocyclic nitrogen.

In another aspect, the present invention provides a mixture comprisingat least two compounds having the formula 1. The at least two compoundshave at least one different R substituent.

In another aspect, the present invention provides a process forpreparing the compound of formula 1. The process comprises:

(a) contacting an acid or ester of formula 2 with a heterocyclic alcoholof formula 3 or a heterocyclic amine of formula 4:

in the presence of an enzyme at conditions effective to form anintermediate of formula 5:

wherein

R, R¹, X, HETN, and n are as defined above,

R⁴ is hydrogen or a C₁-C₆ alkyl group, and

p is 0 or 1 and is chosen to afford a tertiary heterocyclic amine;

(b) contacting the intermediate of formula 5 with an acetic acidalkylating agent at conditions effective to form the compound of formula1.

In yet another aspect, the present invention provides a process forpreparing a mixture comprising at least two compounds having the formula1 wherein the at least two compounds have different R substituents. Theprocess comprises:

(a) contacting a mixture comprising at least two acids or esters offormula 2 with a heterocyclic alcohol of formula 3 or a heterocyclicamine of formula 4:

in the presence of an enzyme at conditions effective to form at leasttwo intermediates of formula 5:

wherein

R, R¹, X, HETN, and n are as defined above,

R⁴ is hydrogen or a C₁-C₆ alkyl group, and

p is 0 or 1 and is chosen to afford a tertiary heterocyclic amine,

the at least two acids or esters of the formula 2 have different Rsubstituents, and

the at least two intermediates of the formula 5 have different Rsubstituents; and

(b) contacting the intermediates of the formula 5 with an acetic acidalkylating agent at conditions effective to form the mixture of at leasttwo compounds of the formula 1.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a series of heterocyclicamphoteric compounds having the formula 1:

wherein

R is a C₃-C₂₃ hydrocarbyl group;

R¹ is a C₁-C₈ hydrocarbyl group;

HETN is a heterocyclic group selected from piperidine, pyridine,pyrollidine, quinoline, tetrahydroquinoline, indole, indoline,octahydroindole, acridine, octahydroacridine, andtetradecahydroacridine;

X is O or NH;

n is 0 or 1; and

m is 0 or 1 and is chosen to afford a quaternary heterocyclic nitrogen.

As used herein, the term “hydrocarbyl” refers to a mono-valenthydrocarbon group. The term includes groups such as alkyls, alkenes,alkynes, aryls, and cycloalkyls.

The hydrocarbyl group of R may be substituted or unsubstituted; branchedor straight-chain; and saturated, mono-unsaturated, or poly-unsaturated.The hydrocarbyl group of R may also be a substituted or unsubstitutedC₃-C₈ cycloalkyl group.

In a preferred embodiment, R is selected from substituted orunsubstituted, branched- or straight-chain, saturated C₅-C₁₉ alkyl;substituted or unsubstituted, branched- or straight-chain C₅-C₁₇alkenyl; substituted or unsubstituted, branched- or straight-chainC₅-C₁₇ dienyl; and substituted or unsubstituted C₃-C₈ cycloalkyl.

The hydrocarbyl group of R may be substituted with one to fivesubstituents selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆carboxyl, C₁-C₁₅ aminocarbonyl, C₁-C₁₅ amido, cyano, C₂-C₆alkoxycarbonyl, C₂-C₆ alkanoyloxy, hydroxy, aryl, heteroaryl, thioether,C₂-C₁₀ dialkylamino, C₃-C₁₅ trialkylammonium, chlorine, and bromine.

As used herein, the terms “C₁-C₆ alkoxy,” “C₂-C₆ alkoxycarbonyl,” and“C₂-C₆ alkanoyloxy” are used to denote radicals corresponding to thestructures —OR²,

—CO₂R², and —OCOR², respectively, where R² is a substituted orunsubstituted C₁-C₆ alkyl group.

As used herein, the terms “C₁-C₁₅ aminocarbonyl” and “C₁-C₁₅ amido” areused to denote radicals corresponding to the structures —NHCOR³ and—CONHR³, respectively, where R³ is a substituted or unsubstituted C₁-C₁₅alkyl group.

As used herein, the term “C₃-C₈ cycloalkyl” is used to denote asaturated, carbocyclic hydrocarbon radical having three to eight carbonatoms.

The hydrocarbyl group of R¹ may be branched or straight-chain;substituted or unsubstituted; and saturated, mono-unsaturated, orpoly-unsaturated. In one embodiment, R¹ is selected from substituted orunsubstituted, straight-chain or branched C₁-C₆ alkyl or alkenyl groups.In another embodiment, R¹ is selected from substituted or unsubstitutedC₃-C₈ cycloalkyl groups.

In a preferred embodiment, R¹ is selected from branched orstraight-chain C₁-C₆ alkyl groups.

The hydrocarbyl radicals of R¹ may be substituted with one to threesubstituents selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆carboxyl, C₁-C₁₅ aminocarbonyl, C₁-C₁₅ amido, cyano, C₂-C₆alkoxycarbonyl, C₂-C₆ alkanoyloxy, hydroxy, aryl, heteroaryl, thioether,C₂-C₁₀ dialkylamino, C₃-C₁₅ trialkylammonium, chlorine, and bromine.

HETN represents a heterocyclic amino group. HETN may be selected frompiperidine, pyridine, pyrollidine, quinoline, tetrahydroquinoline,indole, indoline, octahydroindole, acridine, octahydroacridine, andtetradecahydroacridine. When HETN is aromatic, such as in the case ofpyridine, m is 0, since R¹ is not needed to afford a quaternary nitrogenin the HETN group. Conversely, when HETN is aliphatic, such as in thecase of piperidine, m is 1, since R¹ would be needed to afford aquaternary nitrogen in the HETN group.

Preferred HETN groups include piperidine, pyridine, and pyrollidine.

The RC(O)X(CH₂)_(n)— moiety in formula 1 may be attached to any carbonatom on the heterocyclic group HETN. Preferred positions include the 3-or the 4-position of the heterocyclic ring.

Examples of the compounds of the invention include those represented bythe formula 1 where R is selected from the group consisting of C₅-C₁₉alkyl, C₅-C₁₇ alkenyl, C₅-C₁₇ dienyl, and C₃-C₈ cycloalkyl; R¹ is aC₁-C₆ alkyl group; HETN is selected from the group consisting ofpiperidine, pyridine, and pyrollidine; X is O or NH; n is 0 or 1; and mis 0 or 1 and is chosen to afford a quaternary heterocyclic nitrogen.

Other examples of the compounds of the invention include thoserepresented by the formula 1 where RCO— is octanoyl, decanoyl, lauroyl,myristoyl, or a C₆ to C₂₀ acyl radical derived from coconut oil,hydrogenated coconut oil, or hydrogenated and/or fractionated coconutoil fatty acids; R¹ is methyl; HETN is a 3-piperidine group or a4-piperidine group; X is O or NH; n is 0 or 1; and m is 1. In oneembodiment, RCO— in this set of exemplary compounds is lauroyl.

Additional examples of the compounds of the invention include thoserepresented by the formula 1 where RCO— is octanoyl, decanoyl, lauroyl,myristoyl, or a C₆ to C₂₀ acyl radical derived from coconut oil,hydrogenated coconut oil, or hydrogenated and/or fractionated coconutoil fatty acids; HETN is a 3-pyridine group or a 4-pyridine group; X isO or NH; n is 0 or 1; and m is 0. In one embodiment, RCO— in this set ofexemplary compounds is lauroyl.

Specific examples of the compounds of the formula 1 include(4-cocoyloxy-1-methylpiperidinium-1-yl)acetate,(3-cocoyloxymethyl-1-methylpiperidinium-1-yl)acetate,(4-cocoyloxymethyl-1-methylpiperidinium-1yl)acetate,(4-lauroyloxy-1-methylpiperidinium-1-yl)acetate,(3-lauroyloxymethyl-1-methylpiperidinium-1-yl)acetate,4-(lauroyloxymethylpyridinium-1-yl)acetate,4-(lauramidomethylpyridinium-1-yl)acetate, and(4-lauramido-1-methylpiperidinium-1-yl)acetate.

In various embodiments of the invention, the “C₆ to C₂₀ acyl radical”may be derived from coconut oil, hydrogenated coconut oil, orhydrogenated and/or fractionated coconut oil fatty acids. In which case,the resulting product may be a mixture of two or more compounds of theformula 1 where each compound has a different R substituent. Forexample, the “C₆ to C₂₀ acyl radical” may be derived from hydrogenatedand stripped/fractionated coconut fatty acids. Coconut fatty acidstypically include a mixture of fatty acids, such as C₈, C₁₀, C₁₂, C₁₄,C₁₆, and C₁₈ fatty acids. The fatty acids may be saturated,mono-unsaturated, or poly-unsaturated. The mixture may be hydrogenatedto increase its melting point. In addition, the mixture may be stripped,for example, of the medium-chain fatty acids, such as C₈ and C₁₀ fattyacids, to yield a fraction of predominately long-chain fatty acids, suchas C₁₂-C₁₈ fatty acids. These fractions (either the medium-chain or thelong-chain, for example) may be used to produce the compounds of theinvention. When such fractions are used, the reaction product wouldinclude a mixture of the compounds of the formula 1 where some compoundsmay have, for example, a C₁₂ acyl radical substituent while othercompounds may have a C₁₄ acyl radical substituent, etc.

Thus, in another aspect, the present invention provides a mixturecomprising at least two compounds having the formula 1:

wherein

R is a C₃₋₂₃ hydrocarbyl group;

R¹ is a C₁-C₈ hydrocarbyl group;

HETN is a heterocyclic group selected from piperidine, pyridine,pyrollidine, quinoline, tetrahydroquinoline, indole, indoline,octahydroindole, acridine, octahydroacridine, andtetradecahydroacridine;

X is O or NH;

n is 0 or 1; and

m is 0 or 1 and is chosen to afford a quaternary heterocyclic nitrogen.

The at least two compounds have at least one different R substituent. Inother words, the at least two compounds have different R substituents.

Examples of the compounds in the mixture according to the inventioninclude those represented by the formula 1 where RCO— is selected fromoctanoyl, decanoyl, lauroyl, myristoyl, and a C₆ to C₂₀ acyl radicalderived from coconut oil, hydrogenated coconut oil, or hydrogenatedand/or fractionated coconut oil fatty acids; R¹ is methyl; HETN is a3-piperidine group or a 4-piperidine group; X is O or NH; n is 0 or 1;and m is 1. In one embodiment, the at least two compounds have differentR substituents selected from C₆ to C₂₀ acyl radicals derived fromcoconut oil, hydrogenated coconut oil, or hydrogenated and/orfractionated coconut oil fatty acids. In another embodiment, RCO— in onecompound is lauroyl and RCO— in another compound is myristoyl. In yetanother embodiment, RCO— in one compound is octanoyl and RCO— in anothercompound is decanoyl.

Other examples of the compounds in the mixture according to theinvention include those represented by the formula 1 where RCO— isselected from octanoyl, decanoyl, lauroyl, myristoyl, and a C₆ to C₂₀acyl radical derived from coconut oil, hydrogenated coconut oil, orhydrogenated and/or fractionated coconut oil fatty acids; HETN is a3-pyridine group or a 4-pyridine group; X is O or NH; n is 0 or 1; and mis 0. In one embodiment, the at least two compounds have different Rsubstituents selected from C₆ to C₂₀ acyl radicals derived from coconutoil, hydrogenated coconut oil, or hydrogenated and/or fractionatedcoconut oil fatty acids. In another embodiment, RCO— in one compound islauroyl and RCO— in another compound is myristoyl. In yet anotherembodiment, RCO— in one compound is octanoyl and RCO— in anothercompound is decanoyl.

In another aspect, the present invention provides a process forpreparing a compound of the formula 1. The process may be used toprepare any of the compounds of the formula 1 described herein. Theprocess comprises:

(a) contacting an acid or ester of formula 2 with a heterocyclic alcoholof formula 3 or a heterocyclic amine of formula 4:

in the presence of an enzyme at conditions effective to form anintermediate of formula 5:

wherein

R, R¹, X, HETN, and n are as defined herein above,

R⁴ is hydrogen or a C₁-C₆ alkyl group, and

p is 0 or 1 and is chosen to afford a tertiary heterocyclic amine; and

(b) contacting the intermediate of formula 5 with an acetic acidalkylating agent at conditions effective to form the compound of formula1.

The C₁-C₆ alkyl group of R⁴ may be branched or straight-chain.

The carboxylic acid or ester of the formula 2 may be obtainedcommercially or may be produced by any practical method, including thehydrolysis or solvolysis of triglycerides in the presence of water or alower alcohol and a base, acid, or enzyme catalyst, as is known in theart. The preferred lower alcohols are C₁-C₄ alcohols, such as methanol,ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and isobutanol.

Likewise, the heterocyclic alcohol of the formula 3 and the heterocyclicamine of the formula 4 may be obtained commercially or may be producedby methods known in the art.

The first step of the process involves reacting the heterocyclic alcoholof the formula 3 or the heterocyclic amine of the formula 4 with theacid or ester of the formula 2 in the presence of an enzyme to form thedesired intermediate of the formula 5.

The enzymatic reaction of step (a) may be carried out without an addedsolvent or in the presence of an inert solvent. Examples of inertsolvents include cyclic or acyclic ether solvents (such as diethylether, diisopropyl ether, tert-butyl methyl ether, and tetrahydrofuran),aromatic hydrocarbons (such as benzene, toluene, and xylene), aliphaticor alicyclic, saturated or unsaturated hydrocarbons (such as hexane,heptane, cyclohexane, and limonene), halogenated hydrocarbons (such asdichloromethane, dichloroethane, dibromoethane, tetrachloroethylene, andchlorobenzene), polar aprotic solvents (such as acetonitrile, dimethylformamide, and dimethyl sulfoxide), and mixtures thereof.

In one embodiment, the enzymatic reaction is carried out in the absenceof an added solvent.

In another embodiment, the enzymatic reaction is carried out in thepresence of one or more aromatic or aliphatic hydrocarbons as thesolvent.

The enzymatic reaction may be carried out at a temperature from about−100° C. to the boiling point of the solvent (if employed), preferablyfrom about 20 to 100° C., and more preferably from 50 to 90° C. Theamount of the alcohol 3 or amine 4 may be from 0.85 to 20 equivalents,based on the fatty acid or ester 2, preferably from 1 to 10 equivalents,and more preferably from 1 to 1.5 equivalents.

Step (a) in the process of the invention is desirably carried out in thepresence of an enzyme effective to react the fatty acid or ester 2 withthe alcohol 3 or amine 4 to form the intermediate compound of theformula 5. Effective enzymes for this reaction include lipases. Examplesof these enzymes include, but are not limited to, Lipase PS (fromPseudomonas sp), Lipase PS-C (from Psuedomonas sp immobilized onceramic), Lipase PS-D (from Pseudomonas sp immobilized on diatomaceousearth), Lipoprime 50T, Lipozyme TL IM, Novozyme 435 (lipase from Candidaantarctica immobilized on acrylic resin), and Candida antarctica lipaseB immobilized on a porous fluoropolymer support as described in US2012/0040395 A1. Immobilized enzymes have the advantage of being easilyremoved from the product and re-used.

The enzymatic reaction may be carried out with or without in situ wateror alcohol by-product removal. The water or alcohol by-product can beremoved by any known technique, such as chemically via an alcohol orwater absorbent (e.g., molecular sieves) or by physical separation(e.g., evaporation). This by-product removal is preferably performed byevaporation, either by purging the reaction mixture with an inert gassuch as nitrogen, argon, or helium, or by performing the reaction atreduced pressures, or both, as these conditions can afford >98%conversion of the fatty acid or ester 2 to the intermediate 5. Thepreferred pressure for carrying out the reaction ranges from 1 Torr(133.3 Pa) to ambient pressure, more preferably from 10 Torr (1,333 Pa)to ambient pressure, and most preferably from 50 Torr (6,665 Pa) toambient pressure. Any organic solvent that is included in this step mayor may not be removed along with the alcohol or water. Upon completionof the reaction in step (a), the intermediate 5 of the process may beisolated using methods known to those of skill in the art, e.g.,extraction, filtration, or crystallization.

The second step in the process to generate the final product of theformula 1 involves reacting the intermediate compound of the formula 5with an acetic acid alkylating agent. The acetic acid alkylating agentis typically an acetic acid derivative substituted at the 2-positionwith a leaving group. The leaving group is preferably a halide (e.g.,fluoride, chloride, bromide, etc.). The acetic acid derivative ispreferably neutralized either prior to use or in situ with a base suchas sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium bicarbonate, or potassium bicarbonate. The preferredacetic acid alkylating agent is sodium chloroacetate or chloroaceticacid neutralized in situ with sodium hydroxide.

This step (b) may also be carried out without an added solvent or in thepresence of a solvent. Examples of solvents include water, alcohols anddiols (such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,2-butanol, isobutanol, tert-butanol, tert-pentanol, ethylene glycol,1,2-propanediol, and 1,3-propanediol), cyclic or acyclic ethers (such asdiethyl ether, diisopropyl ether, tert-butyl methyl ether, andtetrahydrofuran), ether-alcohols (such as 2-methoxyethanol,1-methoxy-2-propanol, ethylene glycol monobutyl ether, diethylene glycolmonoethyl ether, diethylene glycol monopropyl ether, and diethyleneglycol monobutyl ether), aromatic hydrocarbons (such as benzene,toluene, and xylene), aliphatic or alicyclic, saturated or unsaturatedhydrocarbons (such as hexane, heptane, cyclohexane, and limonene),halogenated hydrocarbons (such as dichloromethane, dichloroethane,dibromoethane, tetrachloroethylene, and chlorobenzene), polar aproticsolvents (such as acetonitrile, dimethyl formamide, and dimethylsulfoxide), and mixtures thereof. The preferred solvents include water,C₂-C₅ alcohols, ether-alcohols, and mixtures thereof.

The second step may be carried out at a temperature from about −100° C.to the boiling point of the solvent (if employed), preferably from about25 to 150° C., more preferably from 50 to 150° C., and most preferablyfrom 50 to 125° C.

The reaction in the second step may be carried out over a wide range ofpressures. For example, the pressure may range from atmospheric tosuper-atmospheric, e.g., 5 atmospheres or higher.

The amount of acetic acid alkylating agent used is not particularlylimiting. For example, the acetic acid alkylating agent may be used inan amount ranging from 0.75 to 20 equivalents based on the intermediate5, preferably from 1 to 10 equivalents, and more preferably from 1 to1.5 equivalents.

Optionally, a base (in excess of what is needed to neutralize the aceticacid derivative) is included in the reaction mixture of step (b). Ifincluded, the base may be chosen from metal hydroxides, metalcarbonates, and metal bicarbonates. Preferred bases include sodiumcarbonate and sodium bicarbonate. The amount of base used can be from 0molar equivalents to 1 molar equivalent, based on the intermediate ofthe formula 5. The preferred amount is a quantity sufficient to keep thereaction mixture slightly basic, generally a pH of 7.2 or greater.

Upon completion of the reaction in step (b), the intermediate 5 and theproduct 1 of the process may be isolated using methods known to those ofskill in the art, e.g., extraction, filtration, or crystallization.

The process of the invention may be used to prepare a mixture of two ormore compounds of the formula 1. In particular, the process may be usedto prepare any mixture of two or more compounds of the formula 1described herein. As noted above, the two or more compounds of theformula 1 would have different R substituents. If desired, a mixture oftwo or more carboxylic acids or esters of the formula 2, with differentR substituents, may be employed in the enzymatic reaction step (a). Suchmixtures may be derived from, for example, coconut oil, hydrogenatedcoconut oil, or hydrogenated and/or fractionated coconut oil fattyacids. The enzymatic reaction step (a) would yield a mixture of two ormore intermediates of the formula 5, wherein the intermediates 5 wouldhave different R substituents. The mixture of intermediates 5 may thenbe reacted with the acetic acid alkylating agent to produce the mixtureof two or more compounds of the formula 1.

The heterocyclic amphoteric compounds of the formula 1 are particularlyuseful as surfactants. Thus, another aspect of the present inventionrelates to compositions of matter comprising one or more compounds ofthe formula 1 as surfactants. The compositions may contain from 0.001 to20 weight percent of the compounds of the formula 1.

In particular, the heterocyclic amphoteric compounds of the inventionpossess both hydrophilic and hydrophobic regions, making them useful assurfactants in a number of formulated product applications, includingpersonal care products, such as skin care, hair care, and other cosmeticproducts; household and industrial surface cleaners; laundry products;dish cleaners; disinfectants; metal working compositions; rustinhibitors; lubricants; oil field products; oil dispersants;agrochemicals; and dye dispersions. The heterocyclic amphotericcompounds can also be used as emulsifiers and thickening agents inemulsions. The heterocyclic amphoteric compounds can be formulated intoproducts as primary or secondary surface-active agents. Although theirprimary use is as cleansing and foaming agents, the heterocyclicamphoteric compounds can also used for their anti-static,viscosity-controlling, emulsifying, wetting, and dispersing properties.

Such formulated products can contain from about 0.001 weight % to about20 weight %, from about 0.01 weight % to about 15 weight %, or even fromabout 0.1 weight % to about 10 weight % of the heterocyclic amphotericcompounds.

The formulated products of the invention may include other surfactantsin addition to the heterocyclic amphoteric compounds. These othersurfactants can include anionic surfactants (such as alcohol ethersulfates, linear alkylbenzene sulfonates, and acyl isethionates),cationic surfactants (such as quaternary ammonium salts, amine oxides,and ester quats), amphoteric surfactants (such as betaines,amidobetaines, ester betaines, and amphoacetates), and non-ionicsurfactants (such as alky polyglycosides, alcohol ethoxylates, and fattyalcanol amides). Such ingredients are known to those of skill in theart.

As noted, the formulated products of the invention can be cosmetic,skin, and hair care compositions. Those compositions may contain skinconditioning ingredients or cosmetically acceptable carriers in additionto the heterocyclic amphoteric compounds.

Such skin care ingredients/carriers include retinol, retinyl esters,tetronic acid, tetronic acid derivatives, hydroquinone, kojic acid,gallic acid, arbutin, α-hydroxy acids, niacinamide, pyridoxine, ascorbicacid, vitamin E and derivatives, aloe, salicylic acid, benzoyl peroxide,witch hazel, caffeine, zinc pyrithione, and fatty acid esters ofascorbic acid. Other skin care ingredients and carriers are known tothose of skill in the art and may be used in the compositions of theinvention.

Additional ingredients that may be included in these formulationsinclude conditioning agents (such as polyquaterniums and panthenol),pearlizing agents (such as glycol distearate, distearyl ether, andmica), UV filters (such as octocrylene, octyl methoxycinnamate,benzophenone-4, titanium dioxide, and zinc oxide), exfoliation additives(such as apricot seeds, walnut shells, polymer beads, and pumice),silicones (such as dimethicone, cyclomethicone, and amodimethicone),moisturizing agents (such as petrolatum, sunflower oil, fatty alcohols,and shea butter), foam stabilizers (such as cocamide MEA and cocamideDEA), anti-bacterial agents such as triclosan, humectants such asglycerin, thickening agents (such as guar, sodium chloride, andcarbomer), hair and skin damage repair agents (such as proteins,hydrolyzed proteins, and hydrolyzed collagen), and foam boosters such ascocamide MIPA. Such additional ingredients are known to those of skillin the art and may be used in the compositions of the invention.

Many personal care preparations are known in the art. They typicallyinclude acceptable carriers (such as water, oils and/or alcohols),emollients (such as olive oil, hydrocarbon oils and waxes, siliconeoils, other vegetable, animal or marine fats or oils, glyceridederivatives, fatty acids or fatty acid esters), alcohols or alcoholethers, lecithin, lanolin and derivatives, polyhydric alcohols oresters, wax esters, sterols, phospholipids, and the like. These samegeneral ingredients can be formulated into liquids (such as liquidsoaps, shampoos, or body washes), creams, lotions, gels, or into solidsticks by using different proportions of the ingredients and/or byinclusion of thickening agents such as gums or other forms ofhydrophilic colloids. All such preparations may include the heterocyclicamphoteric compounds of the invention.

As used herein, the indefinite articles “a” and “an” mean one or more,unless the context clearly suggests otherwise. Similarly, the singularform of nouns includes their plural form, and vice versa, unless thecontext clearly suggests otherwise.

While attempts have been made to be precise, the numerical values andranges described herein should be considered to be approximations (evenwhen not qualified by the term “about”). These values and ranges mayvary from their stated numbers depending upon the desired propertiessought to be obtained by the present invention as well as the variationsresulting from the standard deviation found in the measuring techniques.Moreover, the ranges described herein are intended and specificallycontemplated to include all sub-ranges and values within the statedranges. For example, a range of 50 to 100 is intended to describe andinclude all values within the range including sub-ranges such as 60 to90 and 70 to 80.

The content of all documents cited herein, including patents as well asnon-patent literature, is hereby incorporated by reference in theirentirety. To the extent that any incorporated subject matter contradictswith any disclosure herein, the disclosure herein shall take precedenceover the incorporated content.

This invention can be further illustrated by the following examples ofpreferred embodiments thereof, although it will be understood that theseexamples are included merely for purposes of illustration and are notintended to limit the scope of the invention.

EXAMPLES Example 1 Preparation of Methyl Cocoate

To a jar was added potassium hydroxide (1 g) and methanol (25 g). Thesolution was stirred for 1 hour. To a separate jar was added coconut oil(100 g). The solid was heated to a melt, and the KOH/MeOH solution wasadded, and the mixture was stirred overnight. The mixture wastransferred to a separatory funnel and allowed to separate. Thebottom/glycerol layer was removed. The top layer was filtered to afforda pale yellow oil (100 g). ¹H NMR (300 MHz, CDCl₃) δ 3.65 (s, 3H), 2.28(t, 2H), 1.60 (m, 2H), 1.24 (s, 16H), 0.86 (t, 3H).

Example 2 Preparation of 1-methyl-4-piperidyl cocoate

To a 250-mL round bottom flask with a magnetic stir bar was added methylcocoate (25 g, 117 mmol), 4-hydroxy-N-methylpiperidine (17.46 g, 152mmol), heptane (10 mL), and Novozyme 435 (2.50 g). A Dean-Stark trap wasplaced onto the flask, and vacuum was applied to the system. The mixturewas heated to 65° C. The heptane azeotrope was utilized to removemethanol by reducing the pressure until the azeotrope distilled overheadinto the Dean-Stark trap to return the heptane to the reaction vessel.After 1.5 hrs, the reaction was stopped. After the mixture was cooled toambient temperature, Novozyme 435 was recovered by filtration. Afterheating to 65° C., nitrogen was bubbled through the mixture to removeany unreacted 4-hydroxy-N-methylpiperidine. ¹H NMR analysis indicated98% conversion to the product, which was isolated as a yellow oil (29.57g). ¹H NMR (300 MHz, CDCl₃) δ 4.78 (m, 1H), 2.66 (m, 2H), 2.32-2.22 (m,7H); 1.95-1.86 (m, 2H); 1.77-1.58 (m, 4H); 1.38-1.25 (m, 18H), 0.88 (t,3H).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 4.7 min.

Example 3 Preparation of (4-cocoyloxy-1-methylpiperidinium-1-yl)acetate

To a 100-mL round bottom flask was added 1-methyl-4-piperidinyl cocoate(10.0 g, 32.1 mmol), sodium chloroacetate (4.30 g, 36.9 mmol), andsodium bicarbonate (540 mg, 6.42 mmol). Water (12.1 mL) and isopropanol(12.1 mL) were then added. The mixture was heated to 80° C. and stirredat this temperature for 19.5 hours. After this time, LC analysisindicated 98.3% conversion. After cooling to ambient temperature, thevolatiles were removed at reduced pressure. Enough water was added backto the flask to obtain ca. 38.75 g of the total mixture. The homogenousmixture was heated to 60° C. while sparging the headspace of the flaskwith 1000 mL/min of nitrogen. Over time, additional water was added tothe solution to maintain 38.75 g of the total mass. After 5 hrs,isopropanol was not observed in the ¹H NMR. After cooling to ambienttemperature, the mixture was filtered through 1-micron filter paper. Theresulting solution was determined to be 28.3 wt %(4-cocoyloxy-1-methylpiperidinium-1-yl)acetate in water by internalstandard ¹H NMR analysis. ¹H NMR analysis was consistent with theproduct structure. HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v)methanol:water (containing 0.1 vol % trifluoroacetic acid) for 10 min,gradient to 100% methanol over 1 min, held at 100% methanol for 9 min,ELSD detection): t_(R) 5.3 min.

Example 4 Preparation of 3-cocoyloxymethyl-N-methylpiperidine

To a 250-mL round bottom flask with a magnetic stir bar was added methylcocoate (69.0 g, 322 mmol), 3-hydroxymethyl-1-methylpiperidine (49.89 g,386 mmol), and Novozyme 435 (10.0 g). The flask was fitted with aseptum, and a needle was inserted to vent. Nitrogen was bubbledsubsurface at a rate sufficient to mix the contents. The mixture washeated to 65° C. After 12 hrs, the sparge rate was increased. At 19.5hrs, ¹H NMR analysis indicated that the reaction was complete. Afterfiltration, the mixture was taken up in Et₂O (750 mL) and subsequentlywashed with water (250 mL×2). The organics were dried with Na₂SO₄. Afterfiltration, the volatiles were removed under reduced pressure to affordthe product as a pale yellow oil (91.67 g). ¹H NMR (300 MHz, CDCl₃) δ3.98 (m, 1H), 3.86 (m, 1H), 2.80 (m, 2H), 2.28 (t, 2H), 2.25 (s, 3H),2.03-1.82 (m, 2H), 1.72-1.55 (m, 5H), 1.33-1.18 (m, 18H), 0.87 (t, 3H).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) 5.1 min.

Example 5 Preparation of(3-cocoyloxymethyl-1-methylpiperidinium-1-yl)acetate

To a 100-mL round bottom flask was added3-cocoyloxymethyl-1-methylpiperidine (10.0 g, 30.8 mmol), sodiumchloroacetate (4.12 g, 35.4 mmol), and sodium bicarbonate (517 mg, 6.16mmol). Water (12.1 mL) and isopropanol (12.1 mL) were then added. Themixture was heated to 80° C. and stirred at this temperature for 25hours. After this time, LC analysis indicated 98.0% conversion. Theresulting mixture weighed 33.9 g and was ca. 31.6 wt %(3-cocoyloxymethyl-1-methylpiperidinium-1-yl)acetate inwater:isopropanol. ¹H NMR analysis was consistent with the productstructure.

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 5.6 min.

Example 6 Preparation of (1-methylpiperidin-4-yl)methyl cocoate

To a 250-mL round bottom flask was added methyl cocoate (50 g, 233mmol), 4-hydroxymethyl-N-methylpiperidine (33.2 g, 257 mmol), andNovozyme 435 (5.0 g). The flask was fitted with a septum, and a needlewas inserted to vent. Nitrogen was bubbled subsurface at a ratesufficient to mix the contents. The reaction mixture was heated to 50°C. After approximately 15 hours, ¹H NMR analysis indicated that thereaction was complete. The reaction mixture was allowed to cool. TheNovozyme 435 was removed by filtration. The material was taken up indiethyl ether (250 mL) and subsequently washed with water (250 mL×2).After drying with Na₂SO₄, the mixture was filtered and concentrated.After dissolving in small amount of dichloromethane, the mixture wasfiltered through a short plug of MAGNESOL filter powder and concentratedto afford the product as a pale yellow oil (57.89 g). ¹H NMR (300 MHz,CDCl₃) δ 3.93 (d, 2H), 2.86 (m, 2H), 2.32-2.27 (m, 5H), 1.91 (t, 3H),1.73-1.56 (m, 5H), 1.41-1.23 (m, 19H), 0.88 (t, 3H).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 5.1 min.

Example 7 Preparation of(4-cocoyloxymethyl-1-methylpiperidinium-1yl)acetate

To a 100-mL round bottom flask was added (1-methylpiperidin-4-yl)methylcocoate (10.0 g, 30.7 mmol), sodium chloroacetate (4.11 g, 35.3 mmol),and sodium bicarbonate (520 mg, 6.14 mmol). Water (12.1 mL) andisopropanol (12.1 mL) were then added. The mixture was heated to 80° C.and stirred at this temperature for 18.75 hours. After this time, HPLCanalysis indicated 99.4% conversion. After cooling to ambienttemperature, the volatiles were removed at reduced pressure. Enoughwater was added back to the flask to obtain ca. 38.5 g of the totalmixture. The homogenous mixture was heated to 60° C. while sparging theheadspace of the flask with 1000 mL/min of nitrogen. Over time,additional water was added to the solution to maintain 38.5 g of thetotal mass. After 5 hrs, isopropanol was not observed in the ¹H NMR.After cooling to ambient temperature, the mixture was filtered through1-micron filter paper. The resulting mixture was ca. 36.4 wt %(4-cocoyloxymethyl-1-methylpiperidinium-1yl)acetate in water. ¹H NMRanalysis was consistent with the product structure.

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 5.6 min.

Example 8 Preparation of 1-methyl-4-piperidinyl laurate

To a 250-mL round bottom flask with a magnetic stir bar was added methyllaurate (25 g, 117 mmol), 4-hydroxy-N-methylpiperidine (17.46 g, 152mmol), heptane (10 mL), and Novozym 435 (2.50 g). A Dean-Stark trap wasplaced onto the flask, and the reaction was placed under vacuum. Themixture was heated to 65° C. The heptane azeotrope was utilized toremove methanol by reducing the pressure until the azeotrope distilledoverhead into the Dean-Stark trap to return the heptane to the reactionvessel. After 3 hrs, GC analysis indicated 98.7% conversion. Thereaction was allowed to cool to ambient temperature. Novozym 425 wasrecovered by filtration. The mixture was taken up in diethyl ether (100mL) and washed with water (100 mL). The organics were dried with Na₂SO₄.After filtration, the volatiles were removed under reduced pressure toafford a pale yellow oil that solidified upon standing (32.09 g). ¹H NMR(300 MHz, CDCl₃) δ 4.78 (m, 1H), 2.65 (m, 2H), 2.32-2.22 (m, 7H);1.95-1.85 (m, 3H); 1.77-1.57 (m, 4H); 1.35-1.23 (m, 17H), 0.88 (t, 3H).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) 4.6 min.

Example 9 Preparation of (4-lauroyloxy-1-methylpiperidinium-1-yl)acetate

To a 150-mL round bottom flask was added 1-methyl-4-piperidinyl laurate(5.00 g, 16.1 mmol), sodium chloroacetate (2.52 g, 21.7 mmol), andsodium bicarbonate (270 mg, 3.21 mmol). Water (2.4 mL) and isopropanol(9.7 mL) were then added. The mixture was heated to 80° C. and stirredat this temperature for 21 hours, at which time HPLC analysis indicated99.2% conversion. ¹H NMR analysis was consistent with the productstructure.

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 5.0 min.

Example 10 Preparation of (1-methylpiperidin-3-yl)methyl laurate

To a 3-neck, 2-L round bottom flask fitted with an overhead stirrer anda Dean-Stark trap with cold-finger condenser was added methyl laurate(302 g, 1.41 mol) and 3-hydroxymethyl-1-methylpiperidine (200 g, 1.56mol). Novozym 435 (30 g) was added, followed by the addition of heptane(120 mL). The internal pressure was reduced to 85 mm Hg and controlledby a vacuum regulator. The mixture was heated to 65° C. After 1.5 hrs,23 mL of methanol had collected in the Dean-Stark trap. At that point,the reaction was cooled to ambient temperature. The mixture was allowedto stand overnight. The following morning, the pressure was once againreduced to 85 mm Hg, and the mixture was heated to 65° C. The reactionwas checked by ¹H NMR after 5.5 hours. Additional3-hydroxymethyl-1-methylpiperidine (9.00 g) was added. After 7.5 hrs,the mixture was cooled to ambient temperature. Then additional3-hydroxymethyl-4-methylpiperidine (17.9 g) was once again added. Thepressure was reduced to 65 mm Hg, and the mixture was heated to 65° C.After 5 hrs, the reaction was stopped. The mixture was filtered, and thesolids were washed with additional heptane. Heptane (500 mL) was addedto the organics, which were then washed with water (1×500 mL). After thelayers were separated, the organics were dried with Na₂SO₄. Afterfiltration, most of the volatiles were removed at reduced pressure. Theremaining material was heated to 50° C. and sparged (subsurface) for ca.24 hrs with nitrogen at 100 mL/min to drive off residual heptaneaffording the title compound as a pale yellow oil (401.7 g) that was98.4% pure by ¹H NMR analysis. ¹H NMR (300 MHz, CDCl₃) δ 3.95 (m, 2H),2.08 (m, 2H), 2.30 (t, J=9 Hz, 2H), 2.27 (s, 3H) 2.01-1.83 (m, 2H);1.77-1.56 (m, 8H); 1.37-1.21 (m, 17H), 0.89 (t, 3H).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 5.0 min.

Example 11 Preparation of(3-lauroyloxymethyl-1-methylpiperidinium-1-yl)acetate

To a jacketed 4-L reactor with overheard stirrer was charged3-lauroyloxymethyl-N-methylpiperidine (694.62 g, 2.13 mol) and sodiumchloroacetate (200 g). Water (2220 mL) was then added. After stirringwas initiated, the jacket set point was adjusted to 97° C. After 2hours, the internal temperature stabilized at 88° C. After 5.75 hours,sodium bicarbonate (71.7 g, 850 mmol) was slowly added over a 35-minuteperiod. After gas evolution had mostly ceased, additional sodiumchloroacetate (136 g) was added. At 21.75 hours of reaction time, HPLCanalysis indicated 99.5% conversion. The resulting pale-yellow solutionweighed 3188 g and was 24.4 wt %(3-lauroyloxymethyl-1-methylpiperidinium-1-yl)acetate in water byinternal standard ¹H NMR. ¹H NMR analysis was consistent with theproduct structure.

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 5.3 min.

Example 12 Preparation of (4-pyridinyl)methyl laurate

To a 125-mL round bottom flask with a magnetic stir bar was added methyllaurate (19.6 g, 92 mmol), 4-hydroxymethylpyridine (10.00 g, 92 mmol),and Novozym 435 (2 g). Heptane was added and the mixture was heated to50° C. and sparged with subsurface nitrogen. After 4 hrs, GC analysisindicated 66% conversion and after 24 h 94% conversion was observed. Thereaction was allowed to proceed for an additional day and then cooled toambient temperature. The mixture was diluted with heptane and toluene,and the Novozym 435 was removed by filtration and the cake was washedwith toluene. The combined filtrate and wash was washed with 1:1 (v:v)methanol:water (30 mL), 3:2 (v:v) 10 vol % aqueous potassiumcarbonate:methanol, and aqueous sodium chloride. The organics were driedwith Na₂SO₄ and concentrated to afford the product (16.90 g; 63%). ¹HNMR (300 MHz, dmso-d₆) δ 8.54 (dd, 2h, J=4.3, 1.6 Hz); 7.33 (m, 2H);5.13 (s, 2H); 2.40 (t, 2H, J=7.3 Hz), 1.6-1.4 (m, 2H); 1.22 (m, 20H),0.84 (t, 3H, J=6.4 Hz).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) 7.1 min.

Example 13 Preparation of (4-lauroyloxymethylpyridinium-1-yl)acetate

Sodium chloroacetate (0.440 g; 3.77 mmol; 1.1 equiv.) and sodiumbicarbonate (58 mg; 0.69 mmol; 0.2 equiv.) were combined in a 20-mL vialwith a magnetic stir bar. Water (1 mL) was added. 4-(Pyridinyl)methyllaurate (1.0 g; 3.43 mmol) was added, followed by 2 mL of isopropanol.The homogeneous mixture was stirred at ambient temperature for 5 days toafford 23% conversion to product. The mixture was then heated to 50° C.for 28 h to afford 78% conversion to4-(lauroyloxymethylpyridinium-1-yl)acetate.

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) 4.95 min.

Example 14 Preparation of (4-pyridinyl)methyl lauramide

To a 125-mL round bottom flask with a magnetic stir bar was added methyllaurate (14.87 g, 69.4 mmol), 4-aminomethylpyridine (7.50 g, 69.4 mmol),and Novozym 435 (1.5 g). Heptane was added and the mixture was heated to50° C. and sparged with subsurface nitrogen at 500 mL/min. After 5.5hrs, the material had solidified, and GC analysis indicated 87%conversion of the methyl laurate to product and no apparentaminomethylpyridine remaining. The mixture was diluted with toluenewhile hot, the Novozym 435 was removed by filtration, and the cake waswashed with toluene. The filtrate was cooled to ambient temperature anddiluted with heptane to afford a thick yellow slurry. The mixture wasfiltered, and the solid was washed with heptane and air-dried to afford4-pyridinylmethyl lauramide (14.75 g; 73%). ¹H NMR (300 MHz, dmso-d₆) δ8.48 (dd, 2h, J=4.4, 1.6 Hz); 8.40 (t, 1H, J=6.0 Hz); 7.22 (dd, 2H,J=4.4, 0.70 Hz); 4.27 (d, 2H, J=6.0 Hz); 2.15 (t, 2H, J=7.3 Hz), 1.6-1.4(m, 2H); 1.22 (m, 20H), 0.85 (t, 3H, J=6.9 Hz).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) 3.7 min.

Example 15 Preparation of (4-lauramidomethylpyridinium-1-yl)acetate

Sodium chloroacetate (0.441 g; 3.79 mmol; 1.1 equiv.) and sodiumbicarbonate (58 mg; 0.69 mmol; 0.2 equiv.) were combined in a 20-mL vialwith a magnetic stir bar. Water (1 mL) was added. 4-(Pyridinyl)methyllauramide (1.0 g; 3.44 mmol) was added, followed by 2 mL of isopropanol.The mixture was very thick so an additional 1 mL of isopropanol wasadded. The resulting mixture was stirred at ambient temperature for 5days to afford 69% conversion to product. The mixture was then heated to50° C. for 28 h to afford >99% conversion to4-(lauramidomethylpyridinium-1-yl)acetate. ¹H NMR (300 MHz, dmso-d₆) δ8.73 (d, 2h, J=6.8 Hz); 8.68 (t, 1H, J=5.8 Hz); 7.81 (d, 2H, J=6.7 Hz);4.84 (s, 2H); 4.50 (d, 2H, J=5.8 Hz); 2.21 (t, 2H, J=7.3 Hz), 1.6-1.4(m, 2H); 1.22 (m, 20H), 0.85 (t, 3H, J=7.0 Hz).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) 3.9 min.

Example 16 Preparation of 1-methyl-4-piperdinyl lauramide

To a 250-mL round bottom flask fitted with a Dean-Stark trap connectedto a cold-finger condenser was added methyl laurate (45.0 g, 210 mmol),4-amino-1-methylpiperidine (25.2 g, 220 mmol), and Novozym 435. Heptane(20 mL) was added to the mixture. The pressure was reduced to 60 mm Hgand controlled by a vacuum regulator. The mixture was heated to 65° C.After 2.5 hrs, solids began to form in the reaction mixture. Thereaction was stopped. Ethyl acetate (200 mL) was added to the mix at 50°C. to dissolve the solids. The mixture was then filtered while hotthrough a frit. After the volatiles were removed at reduced pressure,the solids were triturated with heptane (200 mL) and stirred vigorously.The mixture was then filtered. The solids were placed in a 40° C. vacuumoven with nitrogen sweep overnight to afford the title compound as awhite solid (21.0 g). ¹H NMR (300 MHz, CDCl₃) δ 5.23 (m, 1H); 3.77 (m,1H); 2.75 (m, 2H); 2.27 (s, 3H); 2.16-2.04 (m, 4H), 1.90 (m, 2H), 1.43(m, 1H), 1.33-1.18 (m, 17H), 0.87 (t, 3H).

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 3.8 min.

Example 17 Preparation of (4-lauramido-1-methylpiperidinium-1-yl)acetate

To a 100-mL round bottom flask was added 1-methyl-4-piperdinyl lauramide(20.2 g, 64.9 mmol), sodium chloroacetate (8.70 g, 74.7 mmol), andsodium bicarbonate (1.09 g, 12.9 mmol). Ethanol (44.2 mL) was thenadded. The mixture was heated to 80° C. and stirred at this temperaturefor 14.25 hrs. HPLC analysis indicated 43% conversion. Water (2.21 mL)was then added to the mixture. At 16 hours, HPLC analysis indicated 69%conversion. At 20.75 hrs, HPLC indicated 99.2% conversion. After 2 hrsof additional reaction time, the mixture was cooled and concentrated toafford a sticky solid. Isopropanol (200 mL) was added to dissolve thesolids. The mixture was heated to 65° C. and filtered while hot through1-micron filter paper. The resulting solution was concentrated atreduced pressure. Isopropanol (200 mL) was added and the mixture wasconcentrated again. The solid was placed in a 45° C. vacuum oven withnitrogen sweep and dried overnight to afford(4-lauramido-1-methylpiperidinium-1-yl)acetate (13.14 g). ¹H NMRanalysis was consistent with the product structure.

HPLC (150×4.6 mm Zorbax SB-C8 column, 75:25 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 4.2, 4.4 min.

Surfactant Properties

The surfactant properties of the compounds of the formula 1 can bedetermined by a number of tests including an ASTM foam height test and atest for critical micelle concentration.

The Standard Test Method for Foaming Properties of Surface-Active Agents(ASTM 1173-07) was used to determine the foaming properties of theheterocyclic amphoteric compounds of the formula 1 described herein.This method generates foam under low-agitation conditions and isgenerally used for moderate- and high-foam surfactants. This testgathers data on initial foam height and foam decay. Foam decay providesinformation on foam stability.

The apparatus for carrying out this test includes a jacketed column anda pipet. The jacketed column serves as a receiver, while the pipetdelivers the surface-active solution. Solutions of each surface-activeagent were prepared. The solution of the heterocyclic amphotericcompound to be tested was added to the receiver (50 mL) and to the pipet(200 mL). The pipet was positioned above the receiver and opened. As thesolution fell and made contact with the solution in the receiver, foamwas generated. When the pipet was empty, the time was noted and aninitial foam height was recorded. The foam height was recorded eachminute for five minutes. Exact size specifications for the glassware canbe found in ASTM 1173-07. The foam height results for each heterocyclicamphoteric compound 1 and representative standards are listed below inTables 1 (0.1% concentration) and 2 (1% concentration).

The critical micelle concentration (CMC) was also determined for eachcompound. The CMC is the concentration of surfactant above whichmicelles spontaneously form. CMC is an important characteristic of asurfactant. At surfactant concentrations below the CMC, surface tensionvaries widely with surfactant concentration. At concentrations above theCMC, surface tension remains fairly constant. A lower CMC indicates lesssurfactant is needed to saturate interfaces and form micelles. TypicalCMC values are less than 1 weight percent (10,000 ppm).

The fluorimetric determination of CMC described by Chattopadhyay andLondon (Analytical Biochemistry, Vol. 139, pp. 408-412 (1984)) was usedto obtain the critical micelle concentrations found in Table 3 below.This method employs the fluorescent dye 1,6-diphenyl-1,3,5-hexatriene(DPH) in a solution of the surface-active agent. The analysis is basedon differences in fluorescence upon incorporation of the dye into theinterior of the micelles. As the solution exceeds CMC, a large increasein fluorescence intensity is observed. This method has been found to besensitive and reliable, and has been demonstrated on zwitterionic,anionic, cationic, and uncharged surface-active agents.

TABLE 1 Foam height (cm) at time t (min) at 0.1 wt % concentration Foamheight (cm) at time t (min) 1 g/L (0.1 weight %) t = 0 1 2 3 4 5Standard cocamidopropyl betaine 17.0 16.0 16.0 16.0 ND 15.5 Compoundfrom Example No. 3 16.5 16.0 15.5 15.5 15.5 15.5 5 16.5 16.0 15.5 15.515.0 15.0 7 16.0 14.5 12.5 9.0 6.0 4.0 9 17.0 17.0 16.5 16.5 16.0 16.011 18.5 17.5 17.5 17.0 16.5 16.0 ND = not determined

TABLE 2 Foam height (cm) at time t (min) at 1.0 wt % concentration Foamheight (cm) at time t (min) 10 g/L (1.0 weight %) t = 0 1 2 3 4 5Standard cocamidopropyl betaine 17.5 16.5 ND 16.0 16.0 16.0 Compoundfrom Example No. 3 18.5 18.0 17.5 17.0 17.0 17.0 5 18.0 17.5 17.0 17.017.0 16.5 7 18.0 17.0 17.0 17.0 16.5 16.5 9 16.5 16.0 16.0 15.5 15.515.5 11 19.0 18.0 18.0 17.5 17.5 17.5 ND = not determined

As the data in Tables 1 and 2 indicate, solutions of the amphotericheterocyclic compounds 1 generated large amounts of foam. Examples inwhich the foam height did not significantly decrease over time indicategood foam stability.

TABLE 3 Critical micelle concentrations CMC CMC (ppm) (mM) Standardssodium lauryl sulfate 2386 8.27 ammonium lauryl sulfate 392 1.38cocamidopropyl betaine 24.5 0.069 Compound from Example No.  3 22.90.062  5 23.7 0.062  7 19.2 0.050 11 95.0 0.248 17 566.5 1.54

The data in Table 3 indicate that very low concentrations of theheterocyclic amphoteric compounds 1 are needed to reach the criticalmicelle concentration. These values fall in the range of usefulsurface-active agents, and compare well with standard surfactants.

Stability Properties

It was unexpectedly found that the heterocyclic amphoteric compounds ofthe invention can be more stable at lower pH conditions than thecorresponding amphoteric ester betaines disclosed in US 2012/0277324 A1.For example, as seen in Table 4 below, there was limited loss of theheterocyclic amphoteric compound under extended incubation in pH 4.5water at 50° C. (Example 18), while there was significant loss of thesimilar, but non-heterocyclic ester betaine, even under milderconditions (Comparative Example 2).

Comparative Example 1 Preparation of3-(cocoyloxypropyldimethylammonio)acetate

To a 3-L reactor equipped with a condenser and an overhead stirrer wasadded 3-dimethylaminopropyl cocoate (350.42 g; 1.21 mol), sodiumchloroacetate (155 g, 1.33 mol, 1.1 eq), sodium bicarbonate (20.32 g;0.24 mol; 0.2 equiv) and water (807 g). The reaction mixture was stirredand heated to an internal temperature of 76° C. for 12 hours toafford >98% conversion according to HPLC analysis. The mixture wascooled to ambient temperature, and the pH was adjusted to 6.5 by theaddition of 3 M HCl. The resulting mixture was clarified to afford 1267g of a clear yellow liquid. Analysis of the mixture by HPLC indicated a29.6 wt % solution of 3-(cocoyloxypropyldimethylammonio)acetate inwater. ¹H NMR analysis was consistent with the product structure.

HPLC (150×4.6 mm Zorbax SB-C8 column, 80:20 (v:v) methanol:water(containing 0.1 vol % trifluoroacetic acid) for 10 min, gradient to 100%methanol over 1 min, held at 100% methanol for 9 min, ELSD detection):t_(R) (laurate ester) 3.5 min.

Example 18 Stability study of(4-lauroyloxy-1-methylpiperidinium-1-yl)acetate

The material prepared in Example 9 (20 mL) was combined with 210 mg ofcitric acid hydrate, and the pH was lowered to 4.5 by the addition ofaqueous HCl. The resulting mixture was placed in a 50° C. oven. Sampleswere taken periodically and analyzed for the amount of(4-lauroyloxy-1-methylpiperidinium-1-yl)acetate remaining byquantitative HPLC. The results are in Table 4 below.

Comparative Example 2 Stability study of3-(cocoyloxypropyldimethylammonio)acetate

The material prepared in Comparative Example 1 was adjusted to pH 5 bythe addition of aqueous HCl and then placed in a 45° C. oven. Sampleswere taken periodically and analyzed for the amount of3-(cocoyloxypropyldimethylammonio)acetate remaining by quantitativeHPLC. The results are in Table 4 below.

TABLE 4 Stability of Heterocyclic versus Non-Heterocyclic Ester CarboxyAmphoterics Percent amphoteric remaining Example 18 Comparative Example2 (heterocyclic) (non-heterocyclic) Conditions pH 4.5, 50° C. pH 5, 45°C. Time (weeks) 0 100%  100%  2 98% 74% 6 96% ND 8 85% 73% ND = notdetermined

The invention has been described in detail with particular reference topreferred embodiments thereof, but it will be understood that variationsand modifications can be effected within the spirit and scope of theinvention.

We claim:
 1. A compound having the formula 1:

wherein R is a C₃-C₂₃ hydrocarbyl group; R¹ is a C₁-C₈ hydrocarbylgroup; HETN is a piperidine group; X is O or NH; n is 0 or 1; and m is 0or 1 and is chosen to afford a quaternary heterocyclic nitrogen.
 2. Thecompound according to claim 1, wherein the hydrocarbyl group of R isoptionally substituted with one to five substituents selected from thegroup consisting of C₁-C₆ alkoxy, C₁-C₆ carboxyl, C₁-C₁₅ aminocarbonyl,C₁-C₁₅ amido, cyano, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkanoyloxy, hydroxy,aryl, heteroaryl, thioether, C₂-C₁₀ dialkylamino, C₃-C₁₅trialkylammonium, chlorine, and bromine.
 3. The compound according toclaim 2, wherein the hydrocarbyl group of R is mono-unsaturated orpoly-unsaturated.
 4. The compound according to claim 1, wherein R is aC₃-C₈ cycloalkyl group optionally substituted with one to fivesubstituents selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆carboxyl, C₁-C₁₅ aminocarbonyl, C₁-C₁₅ amido, cyano, C₂-C₆alkoxycarbonyl, C₂-C₆ alkanoyloxy, hydroxy, aryl, heteroaryl, thioether,C₂-C₁₀ dialkylamino, C₃-C₁₅ trialkylammonium, chlorine, and bromine. 5.The compound according to claim 1, wherein the hydrocarbyl group of R¹is optionally substituted with one to three substituents selected fromthe group consisting of C₁-C₆ alkoxy, C₁-C₆ carboxyl, C₁-C₁₅aminocarbonyl, C₁-C₁₅ amido, cyano, C₂-C₆ alkoxycarbonyl, C₂-C₆alkanoyloxy, hydroxy, aryl, heteroaryl, thioether, C₂-C₁₀ dialkylamino,C₃-C₁₅ trialkylammonium, chlorine, and bromine.
 6. The compoundaccording to claim 1, wherein the hydrocarbyl group of R¹ is C₁-C₆ alkylor alkenyl.
 7. The compound according to claim 1, wherein R¹ is a C₃-C₈cycloalkyl group optionally substituted with one to three substituentsselected from the group consisting of C₁-C₆ alkoxy, C₁-C₆ carboxyl,C₁-C₁₅ aminocarbonyl, C₁-C₁₅ amido, cyano, C₂-C₆ alkoxycarbonyl, C₂-C₆alkanoyloxy, hydroxy, aryl, heteroaryl, thioether, C₂-C₁₀ dialkylamino,C₃-C₁₅ trialkylammonium, chlorine, and bromine.
 8. The compoundaccording to claim 1, wherein R is selected from the group consisting ofC₅-C₁₉ alkyl, C₅-C₁₇ alkenyl, C₅-C₁₇ dienyl, and C₃-C₈ cycloalkyl; R¹ isa C₁-C₆ alkyl group; and HETN is a piperidine group.
 9. The compoundaccording to claim 1, wherein RCO— is octanoyl, decanoyl, lauroyl,myristoyl, or a C₆ to C₂₀ acyl radical derived from coconut oil,hydrogenated coconut oil, or hydrogenated and/or fractionated coconutoil fatty acids; R¹ is methyl; HETN is a 3-piperidine group or a4-piperidine group; and m is
 1. 10. The compound according to claim 9,wherein RCO— is lauroyl.
 11. The compound according to claim 1, whereinthe compound is selected from the group consisting of(4-cocoyloxy-1-methylpiperidinium-1-yl)acetate,(3-cocoyloxymethyl-1-methylpiperidinium-1-yl)acetate,(4-cocoyloxymethyl-1-methylpiperidinium-1yl)acetate,(4-lauroyloxy-1-methylpiperidinium-1-yl)acetate,(3-lauroyloxymethyl-1-methylpiperidinium-1-yl)acetate, and(4-lauramido-1-methylpiperidinium-1-yl)acetate.
 12. A process forpreparing a compound having the formula 1:

wherein R is a C₃-C₂₃ hydrocarbyl group; R¹ is a C₁-C₈ hydrocarbylgroup; HETN is a piperidine group; X is O or NH; n is 0 or 1; and m is 0or 1 and is chosen to afford a quaternary heterocyclic nitrogen, theprocess comprising: (a) contacting an acid or ester of formula 2 with aheterocyclic alcohol of formula 3 or a heterocyclic amine of formula 4:

in the presence of an enzyme at conditions effective to form anintermediate of formula 5:

wherein R, R¹, X, HETN, and n are as defined above, R⁴ is hydrogen or aC₁-C₆ alkyl group, and p is 0 or 1 and is chosen to afford a tertiaryheterocyclic amine; and (b) contacting the intermediate of formula 5with an acetic acid alkylating agent at conditions effective to form thecompound of formula
 1. 13. The process according to claim 12, whereinthe enzyme is a lipase.
 14. The process according to claim 13, whereinthe lipase is from Pseudomonas sp or Candida antarctica.
 15. The processaccording to claim 13, wherein the lipase is immobilized on a supportselected from the group consisting of ceramic, diatomaceous earth,acrylic resin, and a porous fluoropolymer.
 16. The process according toclaim 12, wherein step (a) is carried out at a temperature of 50 to 90°C. and a pressure of 10 Torr (1,333 Pa) to ambient pressure.
 17. Theprocess according to claim 12, wherein step (a) is carried out in thepresence of an aromatic or aliphatic hydrocarbon solvent.
 18. Theprocess according to claim 12, wherein step (a) is carried out in theabsence of an added solvent.
 19. The process according to claim 12,which further comprises removing water or alcohol by-product from thereaction mixture during step (a).
 20. The process according to claim 12,wherein step (b) is carried out at a temperature of 50 to 125° C. 21.The process according to claim 12, wherein step (b) is carried out inthe presence of a base selected from the group consisting of metalhydroxides, metal carbonates, and metal bicarbonates.
 22. The processaccording to claim 12, wherein step (b) is carried out in the presenceof a solvent.
 23. The process according to claim 22, wherein the solventis selected from the group consisting of water, C₂-C₅ alcohols,ether-alcohols, and mixtures thereof.
 24. The process according to claim12, wherein the acetic acid alkylating agent is sodium chloroacetate orchloroacetic acid neutralized in situ with sodium hydroxide.
 25. Theprocess according to claim 12, wherein R is selected from the groupconsisting of C₅-C₁₉ alkyl, C₅-C₁₇ alkenyl, C₅-C₁₇ dienyl, and C₃-C₈cycloalkyl; R¹ is a C₁-C₆ alkyl group; and HETN is a piperidine group.26. The process according to claim 12, wherein RCO— is octanoyl,decanoyl, lauroyl, myristoyl, or a C₆ to C₂₀ acyl radical derived fromcoconut oil, hydrogenated coconut oil, or hydrogenated and/orfractionated coconut oil fatty acids; R¹ is methyl; HETN is a3-piperidine group or a 4-piperidine group; and m is
 1. 27. The processaccording to claim 26, wherein RCO— is lauroyl.
 28. The processaccording to claim 12, wherein the compound of the formula 1 is selectedfrom the group consisting of(4-cocoyloxy-1-methylpiperidinium-1-yl)acetate,(3-cocoyloxymethyl-1-methylpiperidinium-1-yl)acetate,(4-cocoyloxymethyl-1-methylpiperidinium-1yl)acetate,(4-lauroyloxy-1-methylpiperidinium-1-yl)acetate,(3-lauroyloxymethyl-1-methylpiperidinium-1-yl)acetate, and(4-lauramido-1-methylpiperidinium-1-yl)acetate.